Project Summary Alzheimer?s disease (AD) is an epidemic with tremendous public health impacts, and cannot be prevented or cured. Randomized controlled trials (RCTs) for AD prevention often use clinical endpoints that take years to manifest (e.g., incident AD) or surrogate endpoints that are costly or invasive (e.g., magnetic resonance imaging [MRI] or cerebrospinal fluid biomarkers). Blood biomarkers represent a clinically applicable alternative surrogate endpoint for RCTs that would be both cost-effective and minimally invasive. Significant evidence supports blood biomarkers as prognostic indicators of cognitive decline and risk of AD in epidemiological studies, but little is known about their value as surrogate endpoints for treatment responses in AD prevention. The long-term goal of our research is to establish blood biomarkers that can be used to personalize AD prevention and treatment. The objective of this study is to investigate blood neuropathological and neurotrophic biomarkers as surrogate endpoints for treatment responses to 3 interventions in older adults with amnestic mild cognitive impairment (aMCI, a prodromal stage of AD): aerobic exercise; cognitive training; and combined aerobic exercise and cognitive training (ACT). We chose these biomarkers for their unique mechanistic associations with cerebral amyloidosis, neurodegeneration and neurogenesis. Our central hypothesis is that blood biomarkers change differently as a result of these 3 interventions and predict cognitive responses to these interventions. This study is built on the ACT Trial (1R01AG055469), a single-blinded, multi-site, 22 factorial Phase II RCT that examines the synergistic effects of a 6-month ACT intervention on cognition and MRI biomarkers (AD-signature cortical thickness and hippocampal volume) (n=128). The ACT Trial will randomize older adults with aMCI equally to 1 of 4 groups (aerobic exercise, cognitive training, ACT, and attention control) for 6 months and then follow them for another 12 months. Cognition will be assessed at baseline, 3, 6, 12, and 18 months, and AD-signature cortical thickness and hippocampal volume will be assessed by MRI at baseline, 6, 12, and 18 months. In this ancillary blood biomarker study, we will enroll 120 ACT Trial participants and measure blood biomarkers at baseline, 3, 6, 12, and 18 months. The specific aims are: (1) Determine the effects of interventions on blood biomarkers over 6 months in aMCI; (2) Evaluate blood biomarkers as surrogate endpoints for predicting cognitive responses to interventions over 18 months in aMCI; and (3; exploratory) Examine the correspondence between changes in blood and MRI biomarkers in response to interventions over 18 months in aMCI. We have established the feasibility of enrollment, retention, and blood collections in an ancillary blood biomarker study in our ongoing RCT of aerobic exercise effects in AD. By examining the synergistic effects of ACT on blood biomarkers and the potential of blood biomarkers as surrogate endpoints for treatment responses, our work will inform and advance strategies to prevent and treat cognitive decline in AD, which can be used to improve the health of those impacted by AD.